Project Summary Neuropathy is an acquired disease that can lead to debilitating chronic pain affecting 7% to 10% of the general population. Among patients with symptomatic neuropathy, sleep disturbances, anxiety and depression are common, negatively impacting quality of life. Diabetes is a leading cause of neuropathy and is expected to become more prevalent as the incidence of diabetes increases. Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect of numerous common chemotherapeutics. Unfortunately, there are no disease modifying therapeutics that can prevent neuropathy or regenerate nerves. While there are palliative treatments for pain symptoms, they are effective in less than 50% of patients and use of opioids is restricted for the most severe cases of chronic pain as they can lead to addiction. Clearly there is a need for safe, effective, well- tolerated drugs to treat painful neuropathy by halting or reversing the underlying pathology of the disease. One promising approach to treating painful neuropathy without opioids is the use of ghrelin, a 28-amino acid acylated peptide hormone. However, it has a short half-life and must be delivered via a constant intravenous infusion to have a therapeutic effect. Extend Biosciences' D-VITylation platform technology is truly enabling for small peptide-based therapeutics that are rapidly cleared from the bloodstream by renal filtration. Our platform harnesses the naturally long half-life of vitamin D and its dedicated binding protein, VDBP. When our vitamin D molecule is conjugated to a biological therapeutic, it dramatically improves the half-life and bioavailability of the drug. In addition, use of the technology should also allow the drug to be self-administered by subcutaneous injection. This would be of significant benefit to patients. In our preliminary experiments, we applied D- VITylation to this promising peptide to generate EXT405 as a therapeutic for neuropathy. Pharmacokinetic data show an extended half-life compared to the native peptide. In this Phase I SBIR, we propose to test the efficacy of EXT405 in a cell-based model of neuropathy as well as in animal models of CIPN and diabetes- induced neuropathy.